This project aims to characterize virus-cell interactions leading to AIDS pathogenesis at the cellular and molecular level; to identify important virus reservoirs and sanctuaries that result in persistent virus infection; to identify HIV interactions with cells of the innate immune system; and to study the mechanisms of innate immune defects in AIDS. Identification of all cell types persistently infected by HIV is of profound importance for the understanding of AIDS pathogenesis and for the development of better treatment regimens. We have identified a subset of CD56+CD3- natural killer (NK) cells in healthy donors that express CD4 and the HIV coreceptors CCR5 and CXCR4. These cells are expanded in the peripheral blood of HIV infected individuals and can be productively infected by both CCR5 and CXCR4-restricted molecular clones of HIV-1 in a CD4-dependent manner. Analysis of samples from HIV infected persons showed that viral DNA is present in purified NK cells and virus could be rescued from these cells after in vitro cultivation. Therefore, these cells are part of the permanent virus reservoir in vivo. To control virus replication and AIDS development, virus propagation in these cells needs to be addressed. We have generated evidence indicating several differences in the regulation of virus production in these cells. Direct infection of these important innate immune cells by HIV may be relevant for the defects in innate immunity observed in AIDS patients. The role of cytokines in HIV propagation in primary cells and tissues has been studied further. HIV coreceptor regulation and intracellular mechanisms are important controls for virus propagation. Cytokine regulation of HIV coreceptor expression is cell type specific.